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PubMed1983

[Quantitative evaluation of the protective action of skin protectors].

The purpose of research was to study and give a comparative evaluation of cystamine, mexamine, ionol, dimethyl--sulfoxide, eugenic acid, castor oil and cholesterol as skin local radioprotectors. Experiments were made on random-bred albino rats. Skin areas 25 mm2 in size on each paw were irradiated. The exposure dose rate was 5 X 10(-3) A/kg (1160 p/min.), the surface dose 6.5 X 10(-1) and 7.7 X 10(-1) Q/kg (2500 and 3000 P respectively). The time period (in days) of weak and severe erythema, dry and moist desquamations was assessed. The most sensitive "critical" components of radiation response which are open to modification with the help of radioprotectors--severe erythema and moist desquamation were revealed. Mexamine, cystamine and ionol produce the most marked effect. The value of their protective effect is 48.3; 40.1 and 32.3 units respectively. Skin radioprotectors possessing not less than 50% efficacy can be introduced into practice. A search for new radioprotectors should be aimed at the investigation of agents with the efficacy of a reduction of radiation injuries by 70% and more.

5-Methoxytryptamine↗
PubMedDate not supplied

[Radioprotective agents in the decontamination of rats poisoned with percutaneously administered mustard gas].

The efficacy of rat skin decontamination by radioprotective agents AET and cystamine were tested. Results were compared to standard decontaminants-alcoholate, clay and fuller's earth. It was found that all the animals decontaminated with standard decontaminants had survived 4 LD50 of poison for 21 days. All the animals poisoned by 6 LD50 had survived for 1 day except for those decontaminated with alcoholate where 50% survived throughout the observation period. Alcoholate and clay protected all, and fuller's earth 70% of animals poisoned by 12 LD50, but no longer than 24 h. AET and cystamine protected all rats from 1.7 LD50 for 3 days, from 1 LD50 for 2 days, and from 2 LD50 for 1 day. When higher doses of poison were used (1.7-6.8 LD50) only partial protection was achieved. Our results support the conclusion that radioprotective agents could be convenient means for improvised decontamination of persons poisoned by sulfur mustard, so additional investigations are necessary.

Animals↗
PubMed1997

Free radical production by Nd:YAG laser photodisruption.

BACKGROUND AND OBJECTIVES: Plasma and cavitation bubble formation during optical breakdown in aqueous media may produce hydroxyl (*OH) radicals. The authors' objectives were to detect *OH produced by a neodymium:yttrium-aluminum-garnet (Nd:YAG) laser photodisruptor and to determine *OH concentration in relation to laser energy. MATERIALS AND METHODS: *OH was assayed by measuring absorbance of triiodide (I3-) in a potassium iodide (KI) solution exposed to optical breakdown by an Nd:YAG laser. The concentration-dependent reduction of radical production in relation to cystamine concentration was evaluated. RESULTS: I3- concentration increased linearly with total irradiation energy and decreased exponentially with increasing cystamine concentration. *OH concentration was calculated using extinction coefficients of I3- and chemical equations relating I3- formation to *OH. CONCLUSIONS: The authors calculated that approximately 4 x 10(-12) moles of *OH are produced in a typical posterior capsulotomy of 100 mJ of total energy. This *OH concentration could produce strand breaks in approximately 0.4% of vitreous hyaluronic acid molecules, but is unlikely to produce clinical effects.

Aqueous Humor↗
PubMed1978

Formation of gamma-glutamyl-epsilon-lysine bridges between membrane proteins by a Ca2+-regulated enzyme in intact erythrocytes.

A rise in the intracellular concentration of Ca2+-ions in human erythrocytes causes the formation of high-molecular-weight membrane protein polymers, cross-linked by gamma-glutamyl-epsilon-lysine side chain bridges. Cross-linking involves proteins at the cytoplasmic side of the membrane (band 4.1, spectrin, and band 3 materials) and the reaction is catalyzed by the intrinsic transglutaminase. This enzyme is regulated by Ca2+-ions and it exits in a latent form in normal cells. The protein polymer, isolated from the membranes of Ca2+-loaded intact human red cells, is heterogeneous in size and may contain as many as 6 moles of gamma-glutamyl-epsilon-lysine cross-links per 100,000 gm of protein. Synthetic compounds, which either compete against the epsilon-lysine cross-linking functionalities of the protein substrates (eg, histamine, aminoacetonitrile, cystamine) or directly inactivate the transamidase (eg, cystamine), inhibit the membrane polymerization reaction in intact human erythrocytes. They also interfere with the Ca2+-induced irreversible shape change from discocyte to echinocyte and inhibit the irreversible loss of membrane deformability. Thus, the transamidase-catalyzed production of gamma-glutamyl-epsilon-lysine cross-links in the membrane may be a common denominator in these cellular manifestations.

Calcium↗
PubMed2006

CYTE-I-HD: phase I dose finding and tolerability study of cysteamine (Cystagon) in Huntington's disease.

Cystamine, an inhibitor of transglutaminases, slows progression of Huntington's disease in the murine model by approximately 20%. Cysteamine, the dimer of cystamine, is an orphan drug approved for the treatment of nephropathic cystinosis and has a similar benefit in the murine model but with a narrower therapeutic window. In a single-center open-label study, we determined the maximum tolerable dose (MTD) and side effects of cysteamine in people with Huntington's disease. Cysteamine was started at a dose of 10 mg/kg per day, divided into four doses, and increased by 10 mg/kg per day weekly until the development of intolerable side effects or a maximum dose of 70 mg/kg per day. Of the 9 subjects, 1 had an MTD of 10 mg/kg per day, 1 had an MTD of 20 mg/kg per day, the maximum dose was 30 mg/kg per day for 2, 40 mg/kg per day for 2, and 50 mg/kg per day for 3. Dose-limiting side effects were motoric impairment in 5 and nausea in 4. The dose found tolerable by 8 of the subjects was 20 mg/kg per day. All had a noticeable hydrogen sulfide odor at doses of 40 mg/kg per day or higher. We conclude that, at a dose of 20 mg/kg per day, cysteamine was tolerable in people with Huntington's disease. Nausea and motoric impairment were the dose-limiting side effects.

Adult↗
PubMed2000

Display of active subtilisin 309 on phage: analysis of parameters influencing the selection of subtilisin variants with changed substrate specificity from libraries using phosphonylating inhibitors.

Many attempts have been made to endow enzymes with new catalytic activities. One general strategy involves the creation of random combinatorial libraries of mutants associated with an efficient screening or selection scheme. Phage display has been shown to greatly facilitate the selection of polypeptides with desired properties by establishing a close link between the polypeptide and the gene that encodes it. Selection of phage displayed enzymes for new catalytic activities remains a challenge. The aim of this study was to display the serine protease subtilisin 309 (savinase) from Bacillus lentus on the surface of filamentous fd phage and to develop selection schemes that allow the extraction of subtilisin variants with a changed substrate specificity from libraries. Subtilisins are produced as secreted preproenzyme that mature in active enzyme autocatalytically. They have a broad substrate specificity but exhibit a significant preference for hydrophobic residues and very limited reactivity toward charged residues at the P4 site in the substrate. Here, we show that savinase can be functionally displayed on phage in the presence of the proteic inhibitor CI2. The free enzyme is released from its complex with CI2 upon addition of the anionic detergent LAS. The phage-enzyme can be panned on streptavidin beads after labelling by reaction with (biotin-N-epsilon-aminocaproyl-cystamine-N'-glutaryl)-l-Ala-l-Ala-l-P ro-Phe(P)-diphenyl ester. Reactions of libraries, in which residues 104 and 107 forming part of the S4 pocket have been randomised, with (biotin-N-epsilon-aminocaproyl-cystamine-N'-glutaryl)-alpha-l-Lys-l-A la-l-Pro-Phe(P)-diphenylester allowed us to select enzymes with increased specific activity for a substrate containing a lysine in P4. Parameters influencing the selection as for instance the efficiency of maturation of mutant enzymes in libraries have been investigated.

Alkanesulfonic Acids↗
PubMed1993

Triphasic vascular effects of thiol compounds and their oxidized forms on dog coronary arteries.

The vascular effects of 2-mercaptoethanol, cysteamine, L-cysteine, glutathione (GSH), cystamine and oxidized GSH (GSSG) on the isometric tension of isolated dog coronary arterial strips were examined, and these effects were compared with the triphasic response induced by dithiothreitol (DTT); a rapid and weak contraction (phase A), an intervening slow relaxation (phase B) and a slowly-developing strong contraction (phase C) which we previously reported. The responses of the arteries induced by 2-mercaptoethanol, cysteamine and L-cysteine consisted of phases A, B and C. The order of contractile potency (ED50 of phase C) was DTT approximately L-cysteine > 2-mercaptoethanol approximately cysteamine, while the order of relaxant potency (ED50 of phase B) was DTT > cysteamine approximately 2-mercaptoethanol. GSSG and cystamine mainly produced relaxation, which corresponded to phase B. The phase C contraction was specific to the reduced forms of thiols, except for GSH, which produced only relaxation. The participation of endothelial cells was not essential for the contracting or relaxing effects of the thiol compounds. The phase C contraction was depressed by W-7, a calmodulin antagonist, while phase A was not. Therefore calmodulin-dependent protein kinases may participate in phase C, not in phase A.

Animals↗
PubMed1997

Selenium speciation in human milk with special respect to quality control.

Selenium- (SE) organo compounds of pooled human milk (7th-14th d after delivery) were separated by centrifugation and subsequent size-exclusion chromatography (SEC) as described in ref. (1). The SEC fractions were used for Se determinations by electrothermal vaporization inductively coupled plasma mass spectrometry (ETV-ICP-MS) in parallel to identification procedures of the organic ligands by two different capillary zone electrophoresis (CZE) methods. Further, the combination of isotachophoresis- (ITP) CZE with ETV-ICP-MS was used for final identifications. Mass balances were carried out at each analytical step for quality assurance. Reinjection experiments were performed to check the stability of Se-organo compounds during the analytical procedure. These quality-control experiments showed that no species transformations took place during the analytical procedure, and the Se species were native in human milk. The identification and quantification of organic ligands were clear and resulted in values of 2 (+/- 0.2) mg/L GSH/GSeH, 2 (+/- 0.22) mg/L cystamine/Se-cystamine, 4 (+/- 0.4) mg/L cystine/ Se-cystine, and 1 (+/- 0.18) mg/L methionine/Se-methionine. Unfortunately, a differentiation between sulfur (S) and Se analogs was not possible with the applied CE methods. The Se values per organic ligand were determined as 2.5 (+/- 0.23) mg/L associated with GSH (as GSeH), 3.1 (+/- 0.31) mg/L associated with cystamine (as Se-cystamine), 5.2 (+/- 0.4) mg/L associated with cystine (as Se-cystine), and 1 (+/- 0.1) mg/L associated with methionine (as Se-methionine).

Chromatography, Gel↗
PubMed2002

Quick measurement of protein sulfhydryls with Ellman's reagent and with 4,4'-dithiodipyridine.

Since its introduction in 1959, Ellman's reagent (5,5'-dithio-bis(2-nitrobenzoic acid)) has been the favorite reagent for spectrophotometric measurement of protein sulfhydryls. Meanwhile however, evidence has accumulated that many protein sulfhydryls give an incomplete reaction with Ellman's reagent, even during prolonged assay times. In the present study, the kinetic problem was solved by including cystamine as a "mediator" between the protein sulfhydryl and Ellman's reagent, as previously applied in an enzymatic thiol assay [9]. As an alternative, 4,4'-dithiodipyridine (DTDP) was used in place of Ellman's reagent. Due to its small size, amphiphilic nature, and lack of charge, DTDP quickly reacts with poorly accessible protein sulfhydryls, without any catalysis by cystamine. The DTDP method and the Ellman/cystamine method were both optimized for maximal sensitivity, minimal sample consumption (detection limit 0.2 nmol mL(-1), determination limit 0.6 nmol mL(-1)), and minimal assay time (5 min). In validation experiments, both methods gave identical results and the measured sulfhydryls/protein matched the expected values. Electronic supplementary material to this paper can be obtained by using the Springer Link server located at http://dx.doi.org/10.1007/s00216-002-1347-2.

Animals↗
PubMed1996

The role of thiols in ATP-dependent transport of S-(2,4-dinitrophenyl)glutathione by rat liver plasma membrane vesicles.

The effect of thiol/disulfide exchange on ATP-dependent S-(2,4-dinitrophenyl)glutathione (GS-DNP) transport was studied in sodium nitrate treated rat liver plasma membrane vesicles. Transport followed Michaelis-Menten kinetics with an apparent Km of 9.6 microM for GS-DNP and 124 microM for ATP. 5,5'-Dithiobis(2-nitrobenzoate) (DTNB) and N-ethylmaleimide (NEM) efficiently inactivated GS-DNP transport activity in a dose- and time-dependent manner. Half-maximal inactivation occurred in 10 min at 40 microM for DTNB and 550 microM for NEM. Inactivation by DTNB was reversed by dithiothreitol. S-(N-Ethyl)maleimyl glutathione and/or ATP-Mg2+, but neither S-(N-ethyl)maleimyl cysteinylglycine nor oxidized glutathione could protect transport activity from inactivation by NEM or cystamine. These results suggest that reactive thiols are located near the active site of the transporter and that S-alkyl and the gamma-glutamyl residues of glutathione are important for protection. Biological disulfides which were tested included cystine, oxidized glutathione, oxidized Coenzyme-A, oxidized lipoic acid, and oxidized lipoamide; cystamine was the most potent reversible inactivator. Molecular oxygen also inactivated transport activity, which was recovered on addition of dithiothreitol, suggesting intramolecular disulfide formation by vicinal thiols. We interpret these results to indicate that the ATP-dependent GS-DNP transporter contains two or more thiols which are necessary for the maintenance of transport activity. The reversible inactivation of the activity by biological disulfides suggests that the transporter may be regulated by thiol/disulfide exchange in vivo.

Adenosine Triphosphate↗
PubMed1977

Studies on the amino groups of myosin ATPase. III. Effect of nucleotides on the fluorescence of beta-naphthoquinone-4-sulfonate bound to amino groups of myosin.

beta-Naphthoquinone-4-sulfonate was used for chemical modification of amino groups of myosin. The reagent was found to affect also the sulfhydryl groups if the reaction was not prevented by previous disulfide exchange with cystamine. When cystamine protection was employed the ATPase (ATP phosphohydrolase, EC3.6.1.3) activity was enhanced in the presence of Mg2+ and decreased in the presence of K+ or Ca2+, a pattern typical of myosin with blocked essential amino groups. On addition of ATP or ADP a blueshift was observed in the fluorescent emission spectrum of beta-naphthoquinone-4-sulfonate bound by myosin, presumably owing to conformational changes in the environment of essential amino groups induced by the binding of nucleotides.

Adenine Nucleotides↗
PubMed1986

Ca2+-dependent inactivation of acetylcholine receptors by an endogenous transglutaminase.

The nicotinic acetylcholine receptor (nAChR) from Torpedo californica and T. marmorata electric tissue polymerises irreversibly when DTE and Ca2+ are added to receptor-rich membranes. The polymerisation is time-dependent and complete within 3 h at 30 degrees C. It can be completely prevented by EGTA or the transglutaminase inhibitor cystamine. Transglutaminase activity can also be monitored with the exogenous substrates [3H]putrescine and dimethylcasein. This assay can also be inhibited by EGTA or cystamine.

Acetylcholine↗
PubMed1982

The effect of sulfhydryl compounds on sister-chromatid exchanges. II. The question of cell specificity and the role of H2O2.

In contrast with earlier reports on the induction of sister-chromatid exchanges (SCEs) by SH compounds in cell lines of the Chinese hamster, cysteine, cysteamine and cystamine did not cause an increase of the SCE frequency in human lymphocyte cultures. Differences in the treatment protocols or variations of the BrdUrd concentration had no effect on the induction of SCEs by these substances. The inclusion of H2O2 and comparative investigations with V79 cells of the Chinese hamster showed that the probable reason for the SCE induction by SH compounds is the inability of the cells to degrade H2O2. Furthermore, for cystamine it became clear that additional effects must exist besides the induction of SCEs through H2O2. The present study underlines the fact that the examination of a substance within one cell system does not necessarily permit a reliable statement about the DNA-damaging property of this substance.

Animals↗
PubMed1977

Synthesis of a disulfide affinity adsorbent for purification of estrogen receptor.

Synthesis of an estrogen affinity adsorbent containing a disulfide linkage between the steroid and stationary matrix permitted facile purification of high affinity estrogen binding proteins. Following affinity chromatography of either antibody directed against estrone 17-carboxymethyloxime - bovine serum albumin or immature calf uterine cytoplasmic estrogen receptor proteins, the specifically bound mercaptoethanol. Crude antibody and uterine cytosol was 10(-3) to 10(-2)M cystamine (S-S) to block SH-containing proteins, in order to protect the adsorbent against protein-mediated S-S in equilibrium SH exchange. Cystamine was found to markedly stabilize crude cytosol receptor protein by 200-300% compared with preparations obtained under ordinary conditions. Disulfide affinity adsorbents are versatile in that they can be used either under conventional conditions of specific protein recovery, or with 2-mercaptoethanol which removes the ligand and bound protein from the stationary matrix quantitatively.

Animals↗
PubMed1995

Bacterial expression of human chorionic gonadotropin alpha subunit: studies on refolding, dimer assembly and interaction with two different beta subunits.

Human chorionic gonadotropin (hCG) is a member of a family of heterodimeric glycoprotein hormones that have a common alpha subunit but differ in their hormone-specific beta subunit. The common alpha subunit contains two asparagine (N)-linked oligosaccharides. To study the function of carbohydrates on in vitro refolding of alpha subunit and dimer assembly, we generated recombinant non-glycosylated hCG alpha subunit (rNGl-hCGalpha) from E. coli. The expression vector was constructed by inserting hCGalpha cDNA coding for the mature form in-frame into a pQE-30 vector, which contains a 6 x His sequence immediately before the 5'-end of hCGalpha cDNA for subsequent purification of rNG-hCGalpha. The rNG-hCGalpha expressed in inclusion bodies was efficiently purified by immobilized metal chelate affinity chromatography on Ni-NTA resin. SDS-PAGE, solid-phase binding assay and immunoblotting demonstrated the expression of rNG-hCG. Its alpha molecular weight on SDS-PAGE was 14.7 kDa under reducing conditions and 15 kDa for a monomer accompanied with some higher molecular weight oligomer under non-reducing conditions. Reconstitution of rNG-hCGalpha with native hCGbeta and oFSHbeta occurred in very low yield under standard conditions. However, the oxidation-reduction system cystamine (1.34 mM) and cysteamine (7.3 mM) facilitated both the refolding of rNG-hCGalpha and reconstitution of rNG-hCGalpha with native hCGbeta to regain partially correct conformation. These were revealed by conformationally sensitive antibody and receptor binding assays. Cystamine and cysteamine were more effective in the recombination of rNG-hCGalpha with oFSHbeta as indicated by a 22-36-fold decrease in the amount required to cause a 50% competitive inhibition in radioreceptor assay. They have no effect on assembly of rNG-hCGalpha with oLHbeta. Our results suggest the carbohydrate moieties confer greater conformational flexibility to the backbone of the beta subunit and the relative rigidity of the beta subunit may serve as a conformational template of the alpha subunit. The present approach has made it possible to prepare the non-glycosylated gonadotropin alpha subunit in adequate amounts for further study on their biological and topographical features in complete absence of carbohydrate.

Amino Acid Sequence↗
PubMed2005

Formulation and surface modification of poly(ester-anhydride) micro- and nanospheres.

This report presents the formulation and surface modification of poly(ester-anhydride) copolymers. Two synthetic schemes were used to generate a variety of copolymers with varying compositions and molecular weights. These polymers were formulated into both micro- and nanospheres using a water-in-oil-in-water double emulsion technique. Microspheres were between 3 and 10 microm in diameter; whereas, nanospheres were between 300 and 500 nm. Finally, both micro- and nanospheres were surface modified using cystamine and quantified, following cystamine reduction, with DTNB (Ellman's reagent). Surface labeling was observed at 0.20-35 micromol/g for microspheres and 0.6-100 micromol/g for nanospheres and followed the expected trend of increased labeling with increased polyanhydride content.

Absorbable Implants↗
PubMedDate not supplied

Poly(l-glutamic acid) Gd(III)-DOTA conjugate with a degradable spacer for magnetic resonance imaging.

The clinical application of macromolecular Gd(III) complexes as MRI contrast agents is impeded by their slow excretion and potential toxicity due to the release of Gd(III) ions caused by the metabolism of the agents. A polymer Gd(III) chelate conjugate with a cleavable spacer has been designed to solve this problem. Poly(l-glutamic acid)-cystamine-[Gd(III)-DOTA] was prepared by the conjugation of DOTA to PGA (MW = 50,000) via cystamine, a cleavable disulfide spacer, followed by the complexation with GdCl(3). A Gd(III) DOTA chelate derivative was readily released from the polymer conjugate in the incubation with cysteine, an endogenous plasma thiol. The conjugate produced significant MRI blood pool contrast enhancement in nude mice bearing OVCAR-3 human ovarian carcinoma xenographs. Less significant contrast enhancement was observed for a small molecular contrast agent, Gd(DTPA-BMA). The pharmacokinetic MRI study showed that the Gd(III) chelate from the conjugate accumulated in the urinary bladder in a similar kinetic pattern to Gd(DTPA-BMA), suggesting that the chelate was released by the endogenous thiols and excreted through renal filtration. The preliminary results suggest that this novel design has a great potential to solve the safety problem of macromolecular MRI contrast agents.

Animals↗
PubMed1997

Intraphagosomal chlorination dynamics and yields determined using unique fluorescent bacterial mimics.

Fluorescein was covalently attached through a cystamine linker group to carboxy-derivatized polyacrylamide microspheres to generate phagocytosable particles containing fluorescent reporter groups. A unique feature of these beads is that the dye was recoverable in near-quantitative yield from intracellular environments by thiol reduction of the cystamine disulfide bond. Fluorescence microscopy indicated that individual neutrophils could bind as many as approximately 20 serum-opsonized beads, although no appreciable cellular association was observed for unopsonized beads. By using methyl viologen to quench external fluorescence, it was demonstrated that 70-90% of the neutrophil-associated fluorescein on opsonized beads was inaccessible to the medium. The particle-bound fluorescein underwent near-stoichiometric conversion to chlorinated derivatives when reacted with HOCl or the cell-free myeloperoxidase (MPO)-H2O2-Cl- system; products were identified by HPLC separation and electrospray ionization mass spectrometry of the recovered dye. Fluorescence changes accompanying phagocytosis were consistent with chlorination of the dye; fluorescence spectrometric and chemical trapping measurements indicated that intraphagosomal chlorination was far more extensive than extracellular chlorination. Yields of recovered chlorofluoresceins determined by HPLC indicated that sufficient HOCl had been produced intracellularly to kill entrapped bacteria. Fluorescein chlorination coincided approximately with phagocytosis and stimulated uptake of O2 by the cells. Demonstration that HOCl is produced within phagosomes in sufficient concentrations to kill bacteria on a time scale associated with death constitutes strong evidence in support of a primary role for HOCl in the microbicidal action of neutrophils.

Blood Bactericidal Activity↗